Silencing of hypoxia-inducible factor-1α promotes thyroid cancer cell apoptosis and inhibits invasion by downregulating WWP2, WWP9, VEGF and VEGFR2

Adaptation to hypoxia is an important process physiologically and pathologically. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) participates in the cancer biology of numerous endocrine tumors, including their proliferation and differentiation. In the present study, the hypothesis that HIF-1 alpha promotes tumorigenesis in thyroid cancer via upregulating angiogenesis-associated markers is investigated. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to examine the expression of HIF-1 alpha in thyroid cancer cell lines, and to detect the expression of WW domain containing E3 ubiquitin protein ligase (WWP)2, WWP9, vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) in MZ-CRC-1 and TT thyroid cancer cells. Cell proliferation was measured using a Cell Count Kit-8. Cell apoptosis and cell cycle was assessed by flow cytometry. Cell invasive ability was examined by Matrigel transwell analysis. RT-qPCR and western blot analyses demonstrated that the mRNA and protein expression levels of HIF-1 alpha were significant higher in MZ-CRC-1 and TT thyroid cancer cells than in another three thyroid cancer cells (P<0.01). HIF-1 alpha knockdown cells demonstrated inhibition of cell proliferation and invasion, arrested cell cycle at the G1 phase, and induction of cell apoptosis. The protein expression levels of WWP2, WWP9, VEGF and VEGFR2 were decreased in HIF-1 alpha knockdown MZ-CRC-1 and TT cells. In conclusion, HIF-1 alpha may be important in cell apoptosis and invasion of thyroid cancer cells, likely through regulating WWP2, WWP9, VEGF and VEGFR2 expression.